rs1753204754

Variant names:

• chr5-93585076-G-A
• rs1753204754
• NM_005654.6:c.53G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-93585076-G-A
• chr5-93585076-G-C
• chr5-93585076-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_005654.6(NR2F1):​c.53G>A​(p.Gly18Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000113 in 881,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G18V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: NR2F1 NM_005654.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.595
• Publications: 0 publications found

Genes affected

NR2F1 (HGNC:7975): (nuclear receptor subfamily 2 group F member 1) The protein encoded by this gene is a nuclear hormone receptor and transcriptional regulator. The encoded protein acts as a homodimer and binds to 5'-AGGTCA-3' repeats. Defects in this gene are a cause of Bosch-Boonstra optic atrophy syndrome (BBOAS). [provided by RefSeq, Apr 2014]

NR2F1-AS1 (HGNC:48622): (NR2F1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the NR2F1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 51 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 4.1652 (above the threshold of 3.09). Trascript score misZ: 4.6855 (above the threshold of 3.09). GenCC associations: The gene is linked to Bosch-Boonstra-Schaaf optic atrophy syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2560488).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR2F1	NM_005654.6	c.53G>A	p.Gly18Asp	missense_variant	Exon 1 of 3	ENST00000327111.8	NP_005645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR2F1	ENST00000327111.8	c.53G>A	p.Gly18Asp	missense_variant	Exon 1 of 3	1	NM_005654.6	ENSP00000325819.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000113 AC: 1 AN: 881366 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 415510

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 16932

American (AMR) AF: 0.00 AC: 0 AN: 4148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6026

East Asian (EAS) AF: 0.00 AC: 0 AN: 5828

South Asian (SAS) AF: 0.00 AC: 0 AN: 19816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3338

European-Non Finnish (NFE) AF: 0.00000126 AC: 1 AN: 793232

Other (OTH) AF: 0.00 AC: 0 AN: 29476

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Benign	0.093	T;T;.;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.87
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.67	.;T;T;T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.0	N;N;.;.
PhyloP100		0.59
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.15	.;N;.;.
REVEL	Uncertain	0.34
Sift	Benign	0.36	.;T;.;.
Sift4G	Benign	0.65	.;T;.;T
Polyphen		0.13	B;B;.;.
Vest4		0.28, 0.27
MutPred		0.25		Loss of catalytic residue at G18 (P = 0.096);Loss of catalytic residue at G18 (P = 0.096);Loss of catalytic residue at G18 (P = 0.096);Loss of catalytic residue at G18 (P = 0.096);
MVP		0.15
ClinPred		0.24	T
GERP RS		1.7
PromoterAI		0.084	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.090
gMVP		0.46
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1753204754; hg19: chr5-92920782;